There is a fundamental gap in our understanding of the mechanism by which the highly pathogenic Ebola virus (EBOV) enters its host cells and initiates infection. Our long-term objectives are to understand, in molecular detail, how EBOV exploits its host cells to gain entry into the cytoplasm, and to contribute to the development of antiviral therapies for EBOV infection. The focus of this particular application is a class of small molecule compounds that we have discovered to be potent and selective inhibitors of EBOV entry. Our central hypothesis is that this class of compounds antagonizes viral entry by binding, either to the viral glycoprotein, GP, or to a host factor that is essential for the entry process. Guided by strong preliminary data, we will test this hypothesis by pursuing two specific aims: 1. What is the structural basis of the antiviral activity of this class of compounds? 2. What are the functional targets of this class of compounds? Relevance to public health: Ebola virus is the cause of an invariably fatal hemorrhagic fever in humans in equatorial Africa, and is also a potential agent of bioterrorism. We expect this work to generate one or more lead compounds and protein targets for developing countermeasures to these highly pathogenic agents. PUBLIC HEALTH RELEVANCE: Ebola virus causes a highly lethal hemorrhagic fever and is considered to be a bioterrorism threat agent. There are currently no antiviral drugs available to treat infections by Ebola virus. We have discovered new inhibitors that block an early step of Ebola virus infection, and we intend to improve these inhibitors and find out exactly how they work.